EP0302793A2 - Dérivés aralkylaminoalkoxyphényls, procédé de préparation et compositions les contenant - Google Patents

Dérivés aralkylaminoalkoxyphényls, procédé de préparation et compositions les contenant Download PDF

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Publication number
EP0302793A2
EP0302793A2 EP88402032A EP88402032A EP0302793A2 EP 0302793 A2 EP0302793 A2 EP 0302793A2 EP 88402032 A EP88402032 A EP 88402032A EP 88402032 A EP88402032 A EP 88402032A EP 0302793 A2 EP0302793 A2 EP 0302793A2
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EP
European Patent Office
Prior art keywords
group
methyl
benzenesulphonyl
isopropyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP88402032A
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German (de)
English (en)
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EP0302793B1 (fr
EP0302793A3 (en
Inventor
Jean Gubin
Pierre Chatelain
Henri Inion
Jean Lucchetti
Jean-Marie Mahaux
Jean-Noel Vallat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Belgium
Elf Sanofi SA
Original Assignee
Sanofi Pharma NV
Sanofi SA
Elf Sanofi SA
Labaz Sanofi NV
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Priority claimed from US07/082,554 external-priority patent/US4957925A/en
Application filed by Sanofi Pharma NV, Sanofi SA, Elf Sanofi SA, Labaz Sanofi NV filed Critical Sanofi Pharma NV
Publication of EP0302793A2 publication Critical patent/EP0302793A2/fr
Publication of EP0302793A3 publication Critical patent/EP0302793A3/en
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to new carboxyclic or heterocyclic derivatives and to a process for preparing them.
  • the invention relates to the novel aminoalkoxy­phenyl derivatives represented by the general formula : in which : B represents a -S-, -SO- or -SO2 group, R1 and R2 which are identical or different, each denote hydrogen, a methyl or ethyl radical or a halogen such as chlorine, bromine or iodine, A denotes a straight- or branched-alkylene radical having from 2 to 5 carbon atoms or a 2-hydroxypropylene radical in which the hydroxy is optionally substituted by a lower alkyl radical, R3 denotes hydrogen or an alkyl radical R4 denotes a pyridyl, phenyl, 2,3-methylenedioxyphenyl or 3,4-methylenedioxy­phenyl radical or a phenyl group substituted with one or more substituents, which may be identical or different, selected from halogen atoms, lower alkyl groups or lower alkoxy groups, Alk denote
  • alkyl denotes straight- or branched-saturated aliphatic hydrocarbon residues having up to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-­hexyl, n-heptyl or n-octyl
  • lower alkyl denotes saturated aliphatic hydrocarbon residues having up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or 1-methylpropyl
  • lower alkoxy denotes a hydroxy group substituted with a lower alkyl group as defined
  • R can denote, in particular, a methyl, ethyl, n-propyl, isopropyl, n-­butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, neopentyl, phenyl, monofluoro-, monochloro- or monobromophenyl, difluoro-, dichloro- or dibromophenyl, monomethyl- or dimethylphenyl, or monomethoxy- or dimethoxyphenyl radical , a methylphenyl radical substituted with a halogen atom or a cyclopropyl radical,
  • A can denote, in particular, a 1,2-ethylene, 1,3-propylene, 2-methyl-­1,3-propylene, 1,4-tetramethylene or 1,5-pentamethylene chain
  • Alk - R4 can denote, in particular, phenyl,
  • a particularly valuable class of compounds of formula(1) are those in which Cy represents a indolizin-3-yl group.
  • Another class compounds are those in which R1 and R2 each are hydrogen.
  • Particularly useful compounds of formula(1) are those in which the chain represents a [N-methyl-N-(3,4-dimethoxy- ⁇ -phenethyl)amino] propyloxy group.
  • R represents an isopropyl or cyclopropyl group.
  • the invention also relates to the pharmaceutically acceptable salts of the compounds of formula(1)formed with an organic or inorganic acid.
  • organic salts of this type there may be mentioned the oxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate, pamoate, succinate, hexamate, bismethylenesalicylate, ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, cin­namate, mandelate, citraconate, aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulphonate and theophylline­acetate, as well as the salts formed with an amino acid such as the lysine or histidine salt.
  • inorganic salts of this type the hydrochloride, hypo­bromide, sulphate, sulphamate, phosphate and nitrate may be mentioned.
  • Another object of the invention relates to the N-oxide derivatives of the compounds of formula(1).
  • the invention relates, at the same time, to all the isomers of the compound of formula(1), the isomers being considered in the dextrorota­tory or laevorotatory form, or in the form of a mixture, for example in the form of a racemic mixture.
  • aminoalkoxyphenyl derivatives of the invention possess exceptional pharmacological properties, especially calcium transport inhibitory properties, as well as bradycardic, hypo­tensive and antiadrenergic properties.
  • the preferred compounds of the invention are those in which B represents a -SO2- group.
  • the compounds of the invention may be useful as potentiators of anticancer drugs.
  • the invention also relates to pharmaceutical or veterinary compositions containing, as active principle, at least one aminoalkoxyphenyl derivative of formula(1) or a pharmaceutically accept­able salt of this derivative, or an N-oxide derivative thereof, in combination with a pharmaceutical vehicle or a suitable excipient.
  • the daily dosage for a human being weighing 60 kg will be between 2 and 500 mg of active principle.
  • the compounds of formula(1) can be obtained: I.
  • B represents a -S- or -SO2- group and A represents an alkylene radical
  • A represents an alkylene radical
  • B′ represents a -S- of -SO2- group
  • Cy, R1 and R2 have the same meaning as above
  • A represents an alkylene radical as defined in the formula(1)
  • X represents a halogen atom, preferably bromine, or an alkylsulphonyloxy group having from 1 to 4 carbon atoms such as for example, methanesulphonyloxy, or an arylsulphonyloxy group having from 6 to
  • the condensation in question is performed at a temperature between room-temperature and the refluxing-temperature of the medium, the acid acceptor being, for example, an alkali metal carbonate or hydroxide or an excess of amine of formula(3).
  • these can be prepared by condensing, in a suitable solvent such as N,N-dimethylformamide and in the presence of a basic agent such as an alkali metal carbonate, for example potassium carbonate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal hydride such as sodium hydride or an alkali metal alcoholate, for example sodium methylate or ethylate, a 4-hydroxyphenyl derivative of formula(4)above with a halogenated alcohol of general formula: Hal-A-OH (7) in which A denotes an alkylene radical as defined in the formula(1)and Hal has the same meaning as above.
  • a basic agent such as an alkali metal carbonate, for example potassium carbonate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal hydride such as sodium hydride or an alkali metal alcoholate, for example sodium methylate or ethylate, a 4-hydroxyphenyl derivative of formula(4)above with a
  • those compounds of formula(4) can be obtained by fixing a 4-O-protected benzenesulphonyl or phenylthio chain to the required carbocycle or heterocycle using a Friedel-Crafts reaction and deprotecting the oxygen in the 4-position of the benzenesulphonyl or phenylthio group by means of classical procedures to regenerate the OH group.
  • the compound of formula(10) is subsequently demethylated using an ethanethiol/aluminium chloride mixture to give a 4-methoxyphenyl derivative of general formula: in which B′, R, R1 and R2 have the same meaning as above which, when heated to about 200°C provides the required compound of formula (4).
  • the compounds of formula (8) are either known compounds having been published in J. Chem. Soc. 1962 pp. 2627-2629 or compounds which can be prepared in accordance with the method described therein.
  • the compound of formula (12) is subsequently demethylated using an appropriate agent for instance hydrobromic acid or an ethanethiol/aluminium chloride mixture to give the required compound of formula (4).
  • 2-Aryl-imidazo[1,2-a]pyridines are known from J. Med. Chem. 8 , p. 305 (1965).
  • the other 2-R-imidazo[1,2-a]pyridines can be obtained in accor­dance with the method described in the aforesaid reference or using classical procedures.
  • the compounds of formula (12) can be obtained from a 2-R-3-halo-imidazo[1,2-a]pyridine and the alkali metal salt of a 4-­methoxy derivative of formula (15).
  • the 4-tosyloxyphenyl derivative of formula(21) or (21′) is subsequently hydrolysed in basic medium for instance in aqueous alkali metal hydroxide to give the required compound of formula(4)in which B′ represents a -S- group.
  • Compounds of formula (20) in which -OTs is replaced by -OCH3 can also be used. In such case the corresponding compound of formula(21) or (21′)is demethylated using for instance hydrobromic acid.
  • the sulphide derivative of formula(21) or(21′)when oxidized with a suitable agent such as hydrogen peroxide in acetic acid or potassium permanganate, provides the compound of formula(21) or(21′) in which B′ represents a -SO2- group, which compound after hydrogenation on a catalyst such as palladium charcoal or platinum charcoal gives the required compounds of formula(4)in which B′ represents a -SO2- group.
  • the compounds of formula(4) in question in which B′ represents a -SO2- group can be obtained from a 3-R-4-halogeno-­cinnoline or a 4-R-3-halogeno-cinnoline by reacting with a benzene­sulphonyl derivative of general formula(20) in which B′ represents a -SO2- group to obtain a compound of formula(21) or(21′)in which B′ represents a -SO2- group which is detosylated as described above to provide the required compound of formula(4).
  • the tosyl derivative of formula (23) is then hydrolysed in a basic medium for instance aqueous alkali metal hydroxide, to provide the required compound of formula(4).
  • 3-Chloromethyl-pyridazine is a known compound having been publish­ed in Khim. Geterot. Sikl. Soedin. 3 , pp. 412-414 (1970).
  • the pyrrolopyridine derivative of formula (24) is then demethyl­ated for instance by using pyridine hydrochloride at 200 - 220°C to provide the required compound of formula(4).
  • the compounds of formula (27) are then demethylated using for ins­tance aqueous iodhydric acid to provide the required compound of formula (4).
  • the compounds of formula (27) in which R7 and R8 are each hydrogen and B′ represents a -SO2- group can be prepared by trea­ting the alkali metal derivative of a 2-R-benzenesulphonate, with a phenyl derivative of formula (26) in the presence of methansulphonic acid/phosphorous pentoxide, in accordance with the method described in Communications, April 1984, p. 323.
  • the compounds of formula (4) in which Cy represents a 2-naphthyl group and B′ represents a -SO2- group can be obtained by reacting a 2-halogenosulphonyl naphthalene with a R1R2-phenol derivative. This sulphonate derivative is then re-arranged in the presence of aluminium chloride to obtain a complex which is treated by an acid such a hydrochloric acid to provide the required compound of formula (4).
  • the cyclopropane derivative of formula (29) is subsequently heated between 100 and 130°C in the presence of a phase transfer cata­lyst such as for instance triphenylphosphine or tricaprylylmethyl ammonium chloride to provide a 4-tosyloxyphenyl derivative of general formula: in which B′, R, R1, R2, R15, R16 and Ts have the same meaning as above and the said 4-tosyloxyphenyl derivative is then detosylated by treat­ment with a basic agent such as an alkali metal hydroxide, to provide the required compound of formula(4).
  • a phase transfer cata­lyst such as for instance triphenylphosphine or tricaprylylmethyl ammonium chloride
  • the compounds of formula (4) in which Cy represents an optionally substituted 2-R-furan-3-yl group can be prepared by oxidizing, for instance with manganese oxide, a sulphide derivative of formula (30) to obtain an optionally substituted 2-R-­3-(4-tosyloxybenzenesulphonyl)furan derivative which is subsequently treated by a basic medium for instance an alkali metal hydroxide, to provide the required compound of formula(4).
  • R represents hydrogen
  • imidazole or benzimidazole is protected in the 1-position with an appropriate N-protecting group for instance a benzyl group which can subsequently be removed, if desired, using classical procedures.
  • the compounds of formula (36) in which R15 represents hydrogen and B′ represents a -SO2- group can be obtained in accordance with the method described in J. Hetero. Chem. 23 , 1363 (1986) by reac­ting a 1-(4-methoxy-benzenesulphonyl)-2-N,N-dimethylaminoethene with hydroxylamine.
  • compounds of formula (36) in which B′ represents a -SO2- group, R15 is other than hydrogen and in which -OCH3 is replaced by -O Tosyl can be used for obtaining the corresponding compounds of formula (4).
  • These 3-substituted -5-R-3-(4-O-Tosyl)-benzenesulphonyl isoxazole derivatives can be prepared in accordance with the method described in Gazz. Chim. Ital. 98 , 656 (1968) i.e. by reacting a benzenesulphonyl-ketone and an hydroxamic acid derivative.
  • the compounds of formula (37) are compounds which can be prepared in accordance with J. Hetero. Chem., 23 , 1363 (1986) i.e. from a N,N-­dimethylaminoethene derivative and hydrazine.
  • the compounds of formula (4) in which Cy represents a 5-R-pyrazol-4-yl group can be directly obtained from a compound of general formula : in which R and Ts have the same meaning as above, and hydrazine in excess.
  • the compounds of formula (38) can be prepared in accordance with the method described in J. Hetero. Chem. 23 , 1363 (1986) cited above.
  • the compounds of formula (43) can be obtained in accordance with the method described in Tetrah. Lett. 1972, p. 2777 i.e. from a sulphonyl-­methylisocyanide and a thioglycolic acid derivative.
  • the compounds of formula (44) can be obtained in accordance with the method described in Tetrahedron Lett. 23 , pp. 2373-2374 (1972) i.e. from a sulphonylmethylisocyanide and an imidazol derivative.
  • the compounds of formula(4) in which Cy represents a 2-R-imidazol-­1-yl or 2-R-benzimidazol-1-yl group can be obtained by reacting a 2-R-­imidazole or 2-R-benzimidazole with a halide of formula(9) in the presence of a Friedel-Crafts catalyst such as aluminium chloride, to provide a compound of general formula : in which B′, R, R1 and R2 have the same meaning as above and R7 and R8 each represent hydrogen or are taken together with the carbon atoms to which they are attached to form a phenyl group.
  • the compound of formula (47) is then demethylated using an appropriate agent for instance an ethanethiol/aluminium chloride mixture to give the required compound of formula(4).
  • the compound of formula(4) in which Cy represents for instance a 2-R-chromon-3-yl group and B′ represents a -SO2- group can be pre­pared by reacting a 2-R-3-halogeno-chromone with a 4-methoxy derivative of formula(9) in which B′ represents a -SO2- group, in the presence of a Friedel-Crafts catalyst such as aluminium chloride, to obtain the chromone derivative of general formula: in which R, R1 and R2 have the same meaning as above, which is optio­nally demethylated using for instance aqueous hydrobromic acid or pyridine hydrochloride, to provide the required compound of formula(4).
  • the compounds of formula(4) in which Cy represents an optionally substituted 5-R-2,3-dihydro-furan-2-one-4-yl can be prepared by react­ing, in basic medium, for instance potassium carbonate, a ketone of formula(18) with a 2-halogenoacetate of general formula: in which Hal, R14 and R15 have the same meaning as above, to obtain a ketoester which is first hydrolysed in basic medium and then treated with a strong acid to provide the carboxylic acid derivative of general formula: in which B′, R, R1, R2 and R14 have the same meaning as above.
  • the compounds of formula (4) in which Cy represents an optionally substituted 5-R-1,3-dihydro-2H-imidazol-2-one-4-yl can be obtained by reacting a 5-R-imidazol-2-one with a halide of formula(9) to obtain a compound of general formula: in which R, R1, R2, R12, R13 and B′ have the same meaning as above which is subsequently demethylated using appropriate procedures such as in the presence of iodhydric acid, pyridine hydrochloride or hydro­bromic acid, to obtain the required compound of formula(4).
  • the compounds of formula(4) in question can be prepared by adapting the method similar to that described in J. Am. Chem. Soc. 68 , p. 2350 (1946).
  • the compounds of formula(1)in which B represents a -S- or -SO2- group and A represents an alkylene radical, preferably those in which A represents a propylene radical, can also be obtained by reacting, in the presence of a basic agent such as an alkali metal carbonate, for example potassium carbonate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal hydride such as sodium hydride or an alkali metal alcoholate, for example sodium methylate or ethylate, a 4-hydroxyphenyl derivative of formula (4) above with a compound of general formula in which X has the same meaning as above and preferably represents chlorine or a benzenesulphonyloxy or p-toluenesulphonyloxy radical, A represents an alkylene radical and R3,Alk,R4 have the same meaning as above, the reaction taking place at a temperature between room-temperature and the refluxing temperature of the medium and in a polar solvent such as methyl
  • the nitrogen atom is preferably protect­ed by a labile group for instance a protecting group which can be elimi­nated in basic medium for example the tertiobutoxycarbonyl (BOC) group.
  • a labile group for instance a protecting group which can be elimi­nated in basic medium for example the tertiobutoxycarbonyl (BOC) group.
  • the compounds of formula (52) are products which are known or which can be prepared by known methods.
  • the compounds of formula(1)in which Cy represents a group (E), A represents an alkylene chain and B represents a -S- or -SO2- group can also be prepared by reacting a 2-R-imidazole or 2-R-benzimidazole with a halide of general formula: in which B′, R1, R2, Hal and X have the same meaning as above and A represents an alkylene chain, in the presence of an acid acceptor such as triethylamine to obtain a compound of general formula: in which B′, R, R1, R2 and X have the same meaning as above, R7 and R8 each represent hydrogen or are taken together with the carbon atom to which they are attached to form a phenyl group and A represents an alkylene chain, which compound is subsequently reacted with an amine of formula (3) to obtain the required compound of formula(1)in the form of a free base.
  • a 2-R-imidazole or 2-R-benzimidazole with a halide of general formula: in which B′, R
  • the compounds of formula(1)in which Cy represents an optionally mono- or di- substituted 2-R-4,5-dihydro-furan-3-yl group, A represents an alkylene chain and B represents a -S- or -SO2- group can be prepared by hydrolysing a cyclopropane derivative of formula (29) in the presence of an aqueous alkali metal hydroxide solution to provide a 4-methoxyphenyl derivative of general formula: in which B′, R, R1, R2, R15 and R16 have the same meaning as above, which is then reacted: -with a dihaloalkane of formula(5)and the resulting product with an amine of formula(3) or - with a compound of general formula (52) , to provide an aminoalkoxy­phenyl derivative of general formula: in which B′, R, R1, R2,R3,R4;Alk,R15 and R16 have the same meaning as above and A represents an alkylene chain.
  • the cyclopropane derivative of formula (56) is subsequently heated between 100 and 130°C in the presence of a phase transfer catalyst such as for instance triphenylphosphine or tricaprylylmethyl ammonium chloride to provide the required 2,3-dihydrofuran derivative of formula(1)in the form of a free base.
  • a phase transfer catalyst such as for instance triphenylphosphine or tricaprylylmethyl ammonium chloride
  • B represents a -SO- group
  • B by treating, with an oxidizing agent, a sulphide of formula(1)in which B represents a -S- group, this compound of formula(1) being in the form of the free base of a salt thereof so as to obtain the required compound in the form of the free base or a salt thereof.
  • the free base thereof can be recovered by treatment with a basic agent such as an alkali metal carbonate for example potassium carbonate or an alkali metal bicarbonate for example sodium bicarbonate.
  • a basic agent such as an alkali metal carbonate for example potassium carbonate or an alkali metal bicarbonate for example sodium bicarbonate.
  • reaction takes place in water or in an organic solvent such as methylene chloride and in the presence of a suitable oxidizing agent such as for example sodium periodate, potassium permanganate or 3-­chloroperbenzoic acid.
  • a suitable oxidizing agent such as for example sodium periodate, potassium permanganate or 3-­chloroperbenzoic acid.
  • mixtures of sulphoxides or sul­phones can be obtained. These mixtures can be separated by conventional procedures for instance by chromatography.
  • the oxyranylmethoxy derivatives of formula (57) are then treated under reflux with an amine of formula (3), this being performed in a polar solvent such as methyl ethyl ketone or in an excess of amine of formula(3) to give the desired compound of formula(1) in the form of the free base in which A represents a 2-hydroxypropylene chain which can be reacted, if desired, with a lower alkyl halide in the presence of a strong base to provide the compound of formula(1) in the form of the free base in which A represents a 2-hydroxypropylene chain in which the hydroxy is substituted by a lower alkyl radical.
  • by-products may be formed in parallel with the compounds of formula (57) above, on this case 4-(3-halo-2-hydroxypropoxy)benzene­sulphonyl derivatives.
  • the compounds of formula(1) thereby obtained in the form of the free base can then be converted to pharmaceutically acceptable salts by reac­tion with a suitable organic or inorganic acid, for example oxalic, maleic, fumaric, methanesulphonic, benzoic, ascorbic, pamoic, succinic, hexamic, bismethylenesalicylic, ethanedisulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, cinnamic, mandelic, citra­conic, aspartic, palmitic, stearic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulphonic or theophyllineacetic acid or with lysine or histidine.
  • a suitable organic or inorganic acid for example oxalic, maleic, fumaric, methanesulphonic, benzoic, ascorbic,
  • N-oxide derivatives of the compounds of formula(1) can be formed by oxidizing the compound of formula(1) in question with an appropriate oxidizing agent for instance hydrogen peroxide or 3-­chloroperbenzoic acid.
  • an appropriate oxidizing agent for instance hydrogen peroxide or 3-­chloroperbenzoic acid.
  • aralkylaminoalkoxybenzenesulphonyl-benzofurans or benzothiophenes in question have shown, at doses as low as 0.1 to 1.5 mg/kg, sub-total inhibition of the ⁇ -adrenergic effect together with an important ⁇ -antiadrenergic action.
  • Such very valuable antiadrenergic properties were also found to be present in compounds similar in structure to the aralkylaminoalkoxy­benzenesulphonyl-benzofurans and benzothiophenes in question but in which the benzofuran or benzothiophene moiety is replaced by another carbocyclic or heterocyclic group.
  • a particularly valuable class of compounds of the invention are those in which B represents a -SO2- group, and Cy repreversreverss a group selected from : -2-R-indolizin-3-yl - benzofuryl, benzothienyl or indolyl more particularly 2-R-benzofur-3-yl, 2-R-benzothien-3-yl, 2-R-indol-3-yl, - quinolinyl such as 2-R-quinolin-3-yl - pyrrolo[1,2-b]pyridazinyl more particularly 6-R-pyrrolo[1,2-b] pyridazin-5-yl - pyrazolo[1,5-a]pyridyl more particularly 2-R-pyrazolo[1,5-a]pyrid-3-­yl - imidazo[1,2-a]pyridyl more particularly 2-R-imidazo[1,2-a]pyrid-3-yl - 4,5-dihydrofur
  • the calcium inhi­bitory activity of the compounds of the invention is at least equal to, of not greater than, that observed in tests performed with the known compounds.
  • the compounds of the present invention a pharmacological spectrum revealing anticalcium and and antiadrenergic components with a balanced inten­sity which is of therapeutic value, for example, for treatment of angina.
  • blocking the receptors involves a risk, depriving the patient suffering from cardiac insufficiency of a compensatory mechanism which he nor­mally brings into play to limit his circulatory insuf­ficiency.
  • This reflex mechanism leads, in particular, to an increase in the force and the speed of contraction of the heart.
  • conse­quence if this system is blocked, the patient suffering from cardiac insufficiency experiences a worsening of his functional breakdown. It is hence logical to con­sider that the use of a blocker whose action is pure and complete will always involve a cardiac risk.
  • the compounds of the invention meet this objective since they show incomplete and type antiadrener­gic properties. They can hence be considered, not as ⁇ -blockers but as adreno-decelerators, that is to say partial antagonists of the ⁇ - and ⁇ -adrenergic reactions, potentially devoid of the disadvantages listed above for ⁇ -blockers.
  • the calcium inhibitory component demonstrated in the compounds of the invention will act as an exceptional complement to the pharmacological spectrum of their cardiovascular action.
  • Compounds which are calcium antagonists act at the level of the cell membrane by selectively preventing calcium from participating in the process of contraction within the arterial cell.
  • the compounds of the invention possessing both an anticalcium component and an ⁇ - and ⁇ -antiadrenergic component will be of funda­mental value, since they are capable of more extensive therapeutic applications than a separate ⁇ -blocker or a separate calcium inhibitor.
  • Compounds of the invention possess an ⁇ and ⁇ -antiadrenergic component reinforced by an oxygen-economizing effect capable of providing a therapeutic effect in man in the syndrome of angina of effort, which can, moreover, be treated by traditional ⁇ -blockers.
  • the major advantage of these compounds will reside in the fact that they may, as a result of their anti-calcium effect, be used in the treatment of angina at rest, a syndrome induced by the appearance of a spasm in the coronary arteries, which is combated at present by compounds such as diltiazem, vera­pamil or nifedipine.
  • the measurement of the inhibition of the contractile response to depolarization by potas­sium, or the measurement of a relaxation of the tonic contraction on potassium depolarization can represent an evaluation of the power of a compound as an inhibitor of the membrane permeability to Ca++ ions.
  • the aorta was removed from male Wistar rats weighing approximately 300g, and cut into strips approximately 40 mm long and 3 mm wide.
  • a tension of 2g was applied to the preparation. This tension was maintained for 60 minutes in the modified Krebs-­bicarbonate solution, and contractions were then induced by replacing the Krebs-bicarbonate solution by a potassium-Krebs solution (17 mM NaCl; 100 mM KCl; 25 mM NaHCO3; 1 mM KH2PO4; 1.2 mM MgSO4; 2.5 mM CaCl2; 11.5 mM glucose; distilled water to 1000ml).
  • a potassium-Krebs solution 17 mM NaCl; 100 mM KCl; 25 mM NaHCO3; 1 mM KH2PO4; 1.2 mM MgSO4; 2.5 mM CaCl2; 11.5 mM glucose; distilled water to 1000ml.
  • the object of this heat is to determine the capacity of the compounds of the invention for reducing the increase in epinephrine-induced increase in blood-pressure (anti- ⁇ effect) and the isoprenaline-induced acceleration in heart rate (anti- ⁇ effect), in dogs previously anaesthetized with pento­barbital and atropinized.
  • the dose of epinephrine (between 3 and 10 ⁇ g/kg) which induced a reproducible increase in the blood-pressure of approximately 133 x 102 Pa and the dose of isoprenaline (1 to 2 ⁇ g/kg) which induced a reproducible increase in the heart rate of approximately 70 beats/min. were first determined.
  • compositions according to the invention can be presented in any form suitable for administration in human or veterinary therapy.
  • administration unit this can take the form of, for example, a coated- or uncoated tablet, hard- or soft-­gelatin capsule, packaged powder, suspension or syrup for oral administration, a suppository for rectal administration or a solution or suspension for parenteral administration.
  • the therapeutic compositions of the invention may contain, per administration unit, for example, from 50 to 500 mg as the weight of active ingredient for oral administration, from 50 to 200 mg of active ingredient for rectal administration and from 50 to 150 mg of ac­tive ingredient for parenteral administration.
  • the therapeutical veterinary compositions of the inven­tion will be prepared by combining at least one of the compounds of formula (1), or a non-toxic addition salt of this compound, with a suitable excipient, it being pos­sible for the latter to consist, for example, of at least one ingredient selected from the following sub­stances: lactose, starches, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water, benzyl alcohol or sweetening agents.
  • the oxalate was formed using 0.530 g of base so obtained and an ethereal solution was oxalic acid.
  • the oxalate was recrystallized from ethyl acetate/methanol/ethyl ether.
  • the desired pro­duct so obtained was purified by chromatography on a silica column using methanol as eluent.
  • the pure base so obtained was then transformed into an oxalate by addition of oxalic acid in ethyl ether.
  • the oily residue was purified by chromatography on a silica column using, as eluent, a dichlorethane/­ methanol 9/1 mixture.
  • the hydrochloride of the base so provided was formed by adding an ethereal solution of hydrogen chloride.
  • the ethereal phase was washed with water, dried on sodium sulphate and filtered. After evaporating the solvent, an oily residue was obtained which was purified by chromatography and a silica column using methanol as eluent.
  • the oxalate was formed by adding oxalic acid in ethyl ether to an ethereal solution of the base so provided.
  • the ethyl ether was eliminated with a rotatory evaporator to obtain 5.3g of an oil which was purified by chromatography on a silica column using methanol as eluent.
  • the base so provided (4.7g) was then transformed into an oxalate in ethyl ether medium and the salt was recrystallized from ethanol.
  • the ethyl ether was then eliminated using a rotatory evaporator and the residue was purified by chromatography on a silica column using methanol as sol­vent to provide 0.100g (30%) of a base.
  • This base was then transformed into an oxalate in ethyl ether by adding an ethereal solution of oxalic acid and the salt so formed was recrystallized from ethanol.
  • N-benzylimidazole was obtained in a yield of 70%.
  • the organic phase was then dried and evaporated and the base so provided ws purified by chromatography on a silica column using an ethyl acetate/­methanol 95/5 mixture.
  • the oxalate was then formed using an ethereal solu­tion of oxalic acid.
  • the ethyl ether was eliminated with a rotatory evaporator and the residue so obtained was purified by chromatography on a silica column.
  • the base so provided was then transformed into an oxalate by adding oxalic acid in ethyl ether.
  • the desired product was then purified by elution chromatography on silica with acetone as eluent.
  • the oil so isolated (yield : about 96%) was then transformed into an acid oxalate in ethyl acetate using an ethereal solution of oxalic acid.
  • the medium was then heated to 140°C for one hour, cooled and poured into 200 ml of iced water.
  • the brownish precipitate which formed was eliminated by filtr­ation and the filtrate was acidified by adding concentrated hydrochloric acid.
  • the medium was then treated with sodium bicarbonate to neutrality and the filtrate was evaporated to dryness.
  • the brownish residual solid was taken up in a dichloromethane/methanol 4/1 mixture and suction-filtrated to eliminate the insoluble matter.
  • the filtrate when concentrated provided 4.75 g of a brownish oil.
  • the extracts were collected and washed with 3 fractions each of 30 ml of water to obtain 3.45 g of a brownish oil.
  • This oil was then purified on a silica column using an ethyl acetate/methanol 75/25 mixture as solvent to provide 2.4 g of an oil.
  • the dihydrochloride was then formed in methanol by adding gaseous hydrochloric acid. The methanol was evaporated off and the residue was taken up in dry ethyl ether and filtered out.
  • the medium was extracted with a dichloromethane diethyl ether mixture, washed, dried on anhydrous sodium sulphate and evaporated. The residue was then purified by chromatography on a silica column using dichlorethane as eluent.
  • the oily residue was then purified by elution chromatography on silica neutralized with diethyl­amine and using acetone as eluent.
  • the acid oxalate was then formed in iso­propyl ether using an ethereal solution of oxalic acid.
  • a solution of 510 ml of a 25%-aqueous solution of potassium carbon­ate was added to a mixture of 60 g (0.264 mol) of 2-naphthalenesulfonyl chloride and 0.264 mol of phenol in 600 ml of acetone. A precipitate formed.
  • the medium was stirred for about 15 hours at room-temperature and then filtered. After washing first with a 1%-sodium hydroxide solution and then with water, the medium was dried and recrystallized from methanol.
  • a mixture of 110ml of methanesulphonic acid and 11g of phosphoric anhydride was heated to about 80°C to complete dissolution of the anhydride. After cooling to room-temperature, 9.5g (0.0425 mol) of sodium 2-isopropyl­benzenesulphonate and 4.6g (0.0425 mol) of anisole were added. The medium was heated at 80°C for 2 hours, cooled to room-temperature and poured onto ice. After extraction with ethyl ether, the ethereal fraction was washed with water, dried on anhydrous sodium sulphate and filtered. The ether was eliminated to obtain 9.8g of a crude product which was purified by chromatography on a silica column (solvent : dichloroethane).
  • the dichloro­ethane was distilled off and the oily residue (25g)was dissolved in 300ml of ethanol. After that, 20ml of 30%-sodium hydroxide were added and the medium was heated at 80°C for 4 hours. The ethanol was eliminated and the residue was taken up in water. The medium was treated with active charcoal, filtered and neutralized with acetic acid. After filtration, the product was washed on the filter with water and dried under vacuum at 60°C to obtain 12.5g of a product which was purified on a silica column using dichloroethane/ethyl acetate 8/2 as eluent.
  • the ethereal fraction was washed with water, dried on anhydrous sodium sulphate and filtered.
  • the ether was then elimi­nated and the oil so obtained was purified by chromatography on a silica column using ethanol as solvent to provide 1.3g of a base (61.9%).
  • the oxalate was then formed in dry ethylether and recrystallized from an ethyl acetate/isopropanol/diisopropyl ether.
  • a capsule containing the following ingredients was prepared : Ingredient mg Compound of the invention 100.0 Starches 99.5 Colloidal silica 0.5 200.0

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EP88402032A 1987-08-07 1988-08-03 Dérivés aralkylaminoalkoxyphényls, procédé de préparation et compositions les contenant Expired - Lifetime EP0302793B1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0382618A2 (fr) * 1989-02-06 1990-08-16 Sanofi Dérivés aminoalkoxyphényle, leur procédé de préparation ainsi que les compositions en contenant
US4994474A (en) * 1986-02-14 1991-02-19 Sanofi Alkyl- or aryl-aminoalkoxy-benzene-sulfonyl indoles
FR2692574A1 (fr) * 1992-06-23 1993-12-24 Sanofi Elf Dérivés hydroxy-4 benzènethio, leur préparation ainsi que leur utilisation pour la préparation de dérivés aminoalkoxybenzènesulfonyles.
EP0350384B1 (fr) * 1988-07-04 1994-05-25 Elf Sanofi Dérivés de sulfonyl indolizine, leur procédé de préparation et leur utilisation comme intermédiaires de synthèse
FR2708604A1 (fr) * 1993-07-30 1995-02-10 Sanofi Elf Utilisation de dérivés de benzènesulfonyl-indole pour la préparation de médicaments.
FR2725133A1 (fr) * 1994-09-30 1996-04-05 Sanofi Sa Composition pharmaceutique de fantofarone pour administration orale
US6514971B1 (en) 1996-03-15 2003-02-04 Zeneca Limited Cinnoline derivatives and use as medicine
EP2281885A1 (fr) 2003-08-27 2011-02-09 Ophthotech Corporation Combination thérapeutique pour le traitement des troubles oculaires néovasculaires
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL87181A (en) * 1987-08-07 1993-08-18 Sanofi Sa Aminoalkoxyphenyl derivatives, their preparation and pharmaceutical and veterinary compositions containing them
FR2642755B1 (fr) * 1989-02-07 1993-11-05 Sanofi
FR2642756B1 (fr) * 1989-02-07 1994-03-04 Sanofi Derives cycloaminoalkoxyphenyle, leur procede de preparation ainsi que les compositions pharmaceutiques ou veterinaires en contenant
FR2692578B1 (fr) * 1992-06-23 1995-06-30 Sanofi Elf Derives d'indolizines, procede de preparation et utilisation pour la preparation de composes aminoalkoxybenzenesulfonyl-indolizines a activite pharmaceutique.
GB9321811D0 (en) * 1993-10-22 1993-12-15 Smithkline Beecham Plc Pharmaceuticals
EP0927035A4 (fr) * 1996-09-13 2002-11-13 Merck & Co Inc Inhibiteurs de thrombine
WO2012143337A1 (fr) * 2011-04-19 2012-10-26 Neurosearch A/S Nouveaux modulateurs de neurotransmission glutamatergique corticale à médiation dopaminergique et par récepteur nmda

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US4117128A (en) * 1976-08-03 1978-09-26 Smithkline Corporation Sulfonyl benzofurans and benzothiophenes having coronary vasodilator activity
US4220645A (en) * 1977-01-03 1980-09-02 Thea (Therapeutique Et Applications) Sa Chromone derivatives
EP0235111A1 (fr) * 1986-02-14 1987-09-02 Sanofi S.A. Dérivés d'indolizine, leur procédé de préparation ainsi que les compositions les contenant

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FI61030C (fi) * 1976-02-19 1982-05-10 Sanofi Sa Foerfarande foer framstaellning av terapeutiskt verkande 2-substituerade-1- eller 3-benzoyl-indolizinderivat
GB1560006A (en) * 1977-08-18 1980-01-30 Laroche Navarron Sa Benzoyl furan derivatives process for their preparation and therapeutic applications thereof
AU537816B2 (en) * 1980-07-01 1984-07-12 Ici Australia Limited Cinnolines having herbicidal properties
AU8165582A (en) * 1981-04-02 1982-10-07 Ici Australia Limited Quinolin derivatives
IL87181A (en) * 1987-08-07 1993-08-18 Sanofi Sa Aminoalkoxyphenyl derivatives, their preparation and pharmaceutical and veterinary compositions containing them

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US4117128A (en) * 1976-08-03 1978-09-26 Smithkline Corporation Sulfonyl benzofurans and benzothiophenes having coronary vasodilator activity
US4220645A (en) * 1977-01-03 1980-09-02 Thea (Therapeutique Et Applications) Sa Chromone derivatives
EP0235111A1 (fr) * 1986-02-14 1987-09-02 Sanofi S.A. Dérivés d'indolizine, leur procédé de préparation ainsi que les compositions les contenant

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JOURNAL OF MEDICINAL CHEMISTRY, vol. 21, no. 2, 1978, pages 182-188, Columbus, Ohio, US; M.T. COX et al.: "Linked aryl aryloxypropanolamines as a new class of lipid catabolic agents" *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4994474A (en) * 1986-02-14 1991-02-19 Sanofi Alkyl- or aryl-aminoalkoxy-benzene-sulfonyl indoles
EP0350384B1 (fr) * 1988-07-04 1994-05-25 Elf Sanofi Dérivés de sulfonyl indolizine, leur procédé de préparation et leur utilisation comme intermédiaires de synthèse
EP0382618A2 (fr) * 1989-02-06 1990-08-16 Sanofi Dérivés aminoalkoxyphényle, leur procédé de préparation ainsi que les compositions en contenant
EP0382618A3 (fr) * 1989-02-06 1991-11-13 Sanofi Dérivés aminoalkoxyphényle, leur procédé de préparation ainsi que les compositions en contenant
FR2692574A1 (fr) * 1992-06-23 1993-12-24 Sanofi Elf Dérivés hydroxy-4 benzènethio, leur préparation ainsi que leur utilisation pour la préparation de dérivés aminoalkoxybenzènesulfonyles.
EP0576347A1 (fr) * 1992-06-23 1993-12-29 Sanofi Dérivés hydroxy-4 benzènethio, leur préparation ainsi que leur utilisation pour la préparation de dérivés aminoalkoxybenzènesulfonyles
US5508431A (en) * 1992-06-23 1996-04-16 Elf Sanofi 4-hydroxyphenylthio derivatives, their preparation and their use for the preparation of aminoalkoxyphenylsulphonyl derivatives
US5401855A (en) * 1992-06-23 1995-03-28 Elf Sanofi 4-hydroxyphenylthio derivatives, their preparation and their use for the preparation of aminoalkoxyphenylsulphonyl derivatives
EP0645375A1 (fr) * 1993-07-30 1995-03-29 Elf Sanofi Utilisation de dérivés de benzène-sulfonyl-indole pour la préparation de médicaments
FR2708604A1 (fr) * 1993-07-30 1995-02-10 Sanofi Elf Utilisation de dérivés de benzènesulfonyl-indole pour la préparation de médicaments.
US5565484A (en) * 1993-07-30 1996-10-15 Sanofi Benzenesulphonylindole derivatives for the preparation of medicines
AU690556B2 (en) * 1993-07-30 1998-04-30 Sanofi Use of benzenesulphonylindole derivatives for the preparation of medicines
FR2725133A1 (fr) * 1994-09-30 1996-04-05 Sanofi Sa Composition pharmaceutique de fantofarone pour administration orale
WO1996010406A1 (fr) * 1994-09-30 1996-04-11 Sanofi Composition pharmaceutique de fantofarone pour administration orale
US6514971B1 (en) 1996-03-15 2003-02-04 Zeneca Limited Cinnoline derivatives and use as medicine
US7087602B2 (en) 1996-03-15 2006-08-08 Astrazeneca Uk Limited Cinnoline derivatives and use as medicine
EP2281885A1 (fr) 2003-08-27 2011-02-09 Ophthotech Corporation Combination thérapeutique pour le traitement des troubles oculaires néovasculaires
EP3168304A1 (fr) 2003-08-27 2017-05-17 Ophthotech Corporation Thérapie combinée pour le traitement des troubles néovasculaires oculaires
US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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FI93215C (fi) 1995-03-10
RU1819260C (ru) 1993-05-30
FI883672A (fi) 1989-02-08
AU2061988A (en) 1989-02-09
YU152188A (en) 1990-04-30
PT88181A (pt) 1989-06-30
SG59866G (en) 1995-09-18
OA09013A (en) 1991-03-31
JPS6470458A (en) 1989-03-15
ZA885782B (en) 1990-04-25
DD278792A5 (de) 1990-05-16
DK435588D0 (da) 1988-08-04
IE61731B1 (en) 1994-11-30
IE882274L (en) 1989-02-07
NO176142B (no) 1994-10-31
SG58994G (en) 1994-10-28
ATE113274T1 (de) 1994-11-15
DE3886298D1 (de) 1994-01-27
EP0302793B1 (fr) 1993-12-15
FI93215B (fi) 1994-11-30
DK438788D0 (da) 1988-08-05
EP0302792A2 (fr) 1989-02-08
IL87181A (en) 1993-08-18
PT88181B (pt) 1995-03-01
MY103905A (en) 1993-10-30
NO883503L (no) 1989-02-08
DK438788A (da) 1989-02-08
CA1335378C (fr) 1995-04-25
ZA885781B (en) 1990-04-25
PL163114B1 (pl) 1994-02-28
PT88180A (pt) 1989-06-30
NO883503D0 (no) 1988-08-05
TNSN88080A1 (fr) 1990-07-10
FI883672A0 (fi) 1988-08-05
EP0302792B1 (fr) 1994-10-26
MA21348A1 (fr) 1989-04-01
RU2032669C1 (ru) 1995-04-10
DE3886298T2 (de) 1994-06-09
EP0302792A3 (en) 1990-11-28
JPH01104038A (ja) 1989-04-21
ATE98643T1 (de) 1994-01-15
CA1335379C (fr) 1995-04-25
NO176142C (no) 1995-02-08
EP0302793A3 (en) 1990-11-28
HUT48870A (en) 1989-07-28
AR246250A1 (es) 1994-07-29
AU620040B2 (en) 1992-02-13
ES2060667T3 (es) 1994-12-01
HU207990B (en) 1993-07-28
DK435588A (da) 1989-02-08
DE3851925T2 (de) 1995-06-08
IL87181A0 (en) 1988-12-30
NZ225625A (en) 1990-09-26
PL274094A1 (en) 1989-05-02
PT88180B (pt) 1995-03-01
AU608873B2 (en) 1991-04-18
PL160574B1 (pl) 1993-03-31
AU2024388A (en) 1989-02-09
DE3851925D1 (de) 1994-12-01
NZ225642A (en) 1990-03-27

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